Acyl-and amino-substituted phenol ethers



United States Patent This invention relates to acyland amino-substituted phenol ethers, and more particularly to compounds having the general structural formula 5 3 Rs O I I I R4 R5 R4 5 wherein X is an amino radical of the formula in which R is hydrogen, lower alkyl, hydroxy-substituted lower alkyl, lower alkoXy-lower alkyl or lower alkenyl and R is hydrogen, lower alkyl, hydroxy-substit uted' lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, lower alkanoyl or hydroxy-substituted lower alkanoyl, attached to the benzene ring in the 4- or S-position,

R is alkyl with 1 to 11 carbon atoms or an unsubstitute or substituted aryl radical,

R is hydrogen, halogen, lower alkyl, lower alkenyl or lower alkoxy,

R is hydrogen or lower alkyl,

R is hydrogen, halogen or lower alkyl, 7

R is halogen, hydroxyl, lower alkoxy, lower alkanoyloxy or halogen-substituted methyl, and

n is a whole number from to 2, inclusive.

The compounds embraced by Formula I above may be prepared by methods customarily employed for the preparation of acyland amino-substituted ethers. The following methods have been found to be particularly suitable:

Method A.-Condensation of acyland amino-substituted phenols of the general formula or their alkali metal salts, wherein X, R and R have the meanings defined above in connection with Formula I, with compounds of the general formula l 1 R4 R R4 R (III) wherein Y is halogen or an aromatic sulfonyl radical and R R R and n have the meanings defined above in connection with Formula I, in the absence of solvents or in aqueous suspension or in the presence of solvents, such as alcohols, aliphatic or aromatic hydrocarbons or aromatic nitro-compounds, in the absence or presence of acid-binding agents, such as alkali metal amides, alkali metal alcoholates, alkali metal hydroxides, alkali metal carbonates, akali metal bicarbonates, alkaline earth metal hydroxides and alkaline earth metal carbonates, advantageouslyat ill characteristics of butanol, the volume of the reactionmix temperatures between 40 and 150 C., preferably at the boiling point of the solvent if one is used.

When compounds of the Formula III are used in which Y is chlorine or bromine, the addition of a catalytic H amount (1/100 to 1/10 equivalent) of potassium iodide is recommended to accelerate the reaction.

It is also advantageous to perform the condensation reaction in an=inert atmosphere, for example-in an atmosphere .of nitrogen, in order to eliminate the oxidizing efiect of oxygen from the air. 7

It has been found to ,be particularly advantageous to perform the condensation reaction in a water-immiscible alcohol, such-as butanol, and in the presence of sodium carbonate or potassium carbonate. The advantages derived therefrom-are that, because of the good solvent ture canbe kept small, the water formed by the reaction can be continuously removed by means of a Water separato'rgandthe progress of the reaction can thus be continuously checked. The carbonates have a very lowresinizing effect because they are relatively weak alkalies.

Moreover, the use of nitrogen as an inert atmosphere is necessary only at the beginning of the reaction under these conditions, because a sufficient amount of carbon dioxide is formed by the reaction to provide the necessary inert atmosphere.

Method B.For the preparation of compounds havin the general Formula I wherein R is hydroxyl:

Addition reaction between acyl-amino-substituted phegeneral formula 1'34 l a CH-CH wherein R and R have the meanings defined above in connection with Formula I in the presence of l/ to l/ 10 mol of an alkali metal salt of the particular acylamino-substituted phenol and, if desired, in the presence of solvents, especially in the presence of those glycols having the structural formula v HO-(JH-EP-OH from WhiCll'fllG alkyleneoxide reactant is derived, at temperatures of 100 to 200 C., preferably at to C.

The following addition reaction conditions have been found to be particularly advantageous: If the alkyleneoxide is introduced dropwisein the liquid state into the reaction vessel, the use ofa good reflux cooler which can be cooled with a cooling brine at a temperature below 0 C., if possible, is recommended. The low-molecularweight alkyleneoxide evaporatesto a great extent when a drop hits the hot liquid reaction mixture; the addition reaction therefore takes place to a substantial degree from the gaseous phase, and it is therefore recommended to agitate the reaction mixture so turbulently that the gas is entrained into the reaction liquid in finely divided form. The reaction proceeds satisfactorily undenthese conditions.

The reaction may also be performed in an autoclave, by adding the alkyleneoxide to an alkaline solution of the acyl-amino-substituted phenol in liquid or gaseous form under pressure,-and then raising the reaction mixture to the desired reaction temperature, accompanied by stirring or shaking.

Method C.For the preparation of compounds having the general Formula I wherein R has the indicated meanings except halogen, hydroxyl or halogen-substituted methyl: a

2,987,546 V a r Condensation of acyl-amino-substituted phenol ethers of the general formula where n Me i an alkali m ta n Rs h he i g efined in connection with Formula pt ha o en, hy xy or alog nu s ut ni hy T e o de r sation reaction is most advantageously performed in the pr se of i ert ga ic solvents a e p ra u at 50 to 200 .C-', and preferably at the boiling point of the solvent. Suitable solvents are, for example, methanol, ethanol, propanol, dioxan, tetrahydrofuran and dimethylform-amide. s

The compounds of the Formula VI which are used as starting materials in this method are prepared in accordance with method A by etherification of the corresponding acyl-amino-substit'uted phenols.

Method D.-For the preparation of compounds of the Formula I, wherein R is halogen, R is halogen-substituted methyl, and n is 0, while the remaining substituents have the defined meaning in connection with Formula Ii Addition of halogen to compounds of the general formula wherein X, R R and K; have the meanings defined above in connection with Formula I; The addition reaction is advantageously carried out in solvents, such as alcohol, chloroform, glacial acetic acid or dimethylformamide, preferably at low temperatures from -20 to '+20 C.

The compounds of the Formula VIII which are used as starting materials in this method are prepared by etherification of the corresponding acyl-amino-substituted phenols with corresponding allyl compounds in accordance with known procedures.

Method E.For the preparation of compounds of the indicated general Formula I, wherein R and R are hy- VIII) drogen:

Reduction of nitro-compounds of the general formula OgN I Ra Ra R (IX) wherein R R R R R and n have the meanings defined above inconnection with Formula I. The reaction is carried out by known methods, for example by reduction with shavings or powder of iron, zinc, tin, aluminum, or magnesium in acid aqueous or alcoholic-aqueous suspension; by reduction with salts of dithionous acid or of hydrosulfuric acid in alcoholic solution; or by reduction, for example with hydrogen and Raney nickel, in rt solvents u a a o o et ah d o dioxan.

r The acyl-nitro-substituted phenol ethers of the Formula IX which are used as starting materials in this method are prepared by etherification of the corresponding acyl-nitro-substituted phenols with compounds of the general formula R4 1 15 I h ia (X) wherein R R R and n have the meanings defined above in connection with Formula I and Y is halogen or an aromatic sulfonyl radical in accordance with known methods. a 7

Method F.For the preparation of compounds having the indicated general Formula L'wherein R and R have the meanings defined in connection with Formula I, except hydrogen:

- Introduction of radicals R and/or R into the amino substituent of compounds of the general formula HrN R4 R5 I l-r I ia 1: (X1) wherein R R R R R and n have the meanings previously defined in connection with Formula 1. Compounds XI may be prepared by method E above, for exa p The introduction of radicals R and/or R into the amino substituent may be carried out in accordance with known methods, such as by reaction of Compounds XI with corresponding halides, sulfates, or sulfonates in the presence of condensation agents, such as alkali metal hydroxides, alkali metal carbonates, alkali metal amides or alkali metal alcoholates, in aqueous suspension or in inert organic solvents, such as alcohols or hydrocarbons. Monoor di-substitution of the amino radical may be achieved thereby. I-Iydroxyalkyl substitution may also be efiected with the aid of an alkyleneoxide under the conditions set forth in method B above.

If R means a lower alkanoyl or a lower hydroxysubstituted alkanoyl radical, its introduction may be carried out by known methods, for example by reaction of Compounds X1 or by reaction of Compounds 1, wherein R is hydrogen, with chlorides, anhydrides or simple esters of lower alkyl carboxylic acids or lower hydroxyalkyl carboxylic acids;

Method G.-In those cases where methods A through F yield compounds of the Formula I wherein R is a hydroxyl radical, they may, if desired, be further reacted as described below, whereby compounds of the Formula I, wherein R is a lower alkanoyloxy radical, are obtained:

Condensation of compounds having the general structural formula wherein X, R R R R 'and n have the meanings defined above in connection with Formula I, with halides, simple esters or anhydrides of lower alkyl carboxylic acids in the presence or absence of solvents and, if desired, in the presence of a condensation agent, such as an alkali metal hydroxide, alkali metal carbonate, alkali metal amide, alkali metal alcohqlate or alkali metal salt of the acid to be introduced, preferably at temperatures from 0 to 200 C.

If R and R are hydrogen or lower alkyl, alkenyl hydroxyalkyl or alkoxyalkyl the compounds having structural Formula I may be prepared in the form of their acid addition salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic acids, such as acetic acid, lactic acid, citric acid and the like, by well known procedures.

The compounds embraced by Formula I exhibit excellent antipyretic, antiphlogistic and analgesic properties; for example, they are superior in regard to these properties to phenacetin (p-ethoxy-acetanilide). A considerable advantage of the compounds according to the invention resides in that they cause less of a methemoglobin formation in the organism than phenacetin. The pharmacological effect of the novel ethers disclosed herein also exceeds that of the acylamino-substituted phenols disclosed in the prior art.

The following examples will further illustrate the present invention without limiting it.

EXAMPLE 1 Preparation of Z-acetyl-4-acetaminophenyl-B- methoxy-ethyl ether by method A 193 gm. (1.0 mol) 2-acety1-4-acetamino-phenol, 138 gm. (1.0 mol) potassium carbonate and 1500 cc. n-butanol were placed into a 3-neck round-bottom flask provided with a stirring device, a water-separator, a reflux cooler, a gas feed-line and a dropping funnel. The mixture was then heated to the boiling point and boiled until an amount of water corresponding approximately to the initial moisture content of the mixture had separated in the water-separator. Thereafter 230 gm. (0.1 mol) p-toluenesulfonic acid-fi-methoxy-ethyl ester were added to the mixture over a period of /2 hour, and the resulting reaction mixture was refluxed for four additional hours, whereby the water formed by the reaction separated out in the water-separator. The butanol was then distilled ofi in vacuo and the hot liquid residue was poured into ice-cold water, accompanied by stirring. The water contained a small amount of sodium hydroxide to dissolve out any unreacted 2-acetyl-4-acetamino-phenol which may be present in the reaction mixture. The mixture was then filtered on a vacuum filter and the filter cake was washed with water and recrystallized from 50% aqueous methanol. The reaction product, having the structural formula and a melting point of 114 C., was obtained in the form of long, colorless needles.

EXAMPLE 2 Preparation 0 2-acetyl-4-acetaminophenyl-l3- hydroxy-propyl ether by method B 50 gm. 1,2-propylene-glycol, 38.6 gm. (0.2 mol) 2- acetyl-4-acetamino-phenol and 1 cc. of a 40% aqueous sodium hydroxide solution (0.01 mol) were placed into a 3-neck, round-bottom flask provided with a stirring device, reflux cooler and dropping funnel, and the mixture was heated to 125 C. Thereafter, while turbulently stirring the mixture, 12.75 gm. (0.22 mol) propylene oxide were added dropwise at a rate such that a gentle reflux was continuously maintained. The completed etherification reaction was indicated by the fact that toward the end of the reaction the excess of propyleneoxide was no longer absorbed as rapidly as atthe beginning of the reaction and 6 the reflux ceased. The reaction mixture was then diluted with Water to 3 times its volume, made alkaline with sodium hydroxide to dissolve out any unreacted 2-acetyl-4- acetamino'phenol and filtered on a vacuum filter. The filter cake was washed with water and recrystallized from water. The reaction product, having the structural formula II. NHC--CHa u OCHa CHaCH-OH and a melting point of 153 to 154 C., was obtained in the form of long, white needles.

EXAMPLE 3 Preparation of Z-propionyl-4-acetaminophenyl-B- acetoxy-ethyl ether by method C 13.0 gm. 2-propionyl-4-acetaminophenyl-fi-chloroethyl ether (produced from 2-propionyl-4-acetamino-phenol and p-toluene-sulfonic acid-,S-chloroethyl ester in the presence of an alkali) were dissolved in 50 cc. dimethylformamide, and after adding 13 gm. potassium acetate to the solution the resulting mixture was heated under reflux for 5 hours. Thereafter, 2 liters of ice water were poured into the reaction mixture. A crystalline substance separated out after a short period of time which was filtered OH on a vacuum filter. The filter cake, consisting of 15 gm. of the raw moist reaction product, was recrystallized from a 50% aqueous methanol solution, yielding 7.0 gm. (49.5% of theory) 2-propionyl-4-acetaminophenyl-flacetoxy-ethyl ether having the structural formula and a melting point of 101 to 103 C. in the form of white crystals.

EXAMPLE 4 Preparation of 2-acetyl-4-acetamin0-phenyZ-fi,'y-dibr0m0- propyl ether by method D 5.0 gm. 2-acety1-4-acetaminophenyl-allyl ether (produced from 2-acetyl-4-acetamino-phenol and allyl chloride in the presence of an alkali) were dissolved in 250 cc. glacial acetic acid, and the resulting solution was cooled to 15 C., accompanied by stirring. 34.4 gm. bromine were then added dropwise and very slowly to the cooled solution, and after the reaction had gone to completion the reaction mixture was poured into ice water. The reaction product, which separated out at first as an oily substance, crystallized after a few minutes and was then separated on a Vacuum filter. The filter cake was recrystallized twice from isopropancl, yielding 42.0 gm. of a compound having the structural formula Ii lTIH-C- 0 H3 7 and a melting point of 125 C. in the form of white crystals'. EXAMPLE Preparation of 2-acetyl-4-acetaminophenyl-fi-methoxy ethyl ether by methods E and F 17.0 gm. (0.0712 mol) 2-acetyl-4-nitrophenyl-B-methoxy-ethyl ether (prepared from 2-acetyl-4-nitro-phenol and p-toluene-sulfonic acid-B-methoxy-ethyl ester) were dissolved in 100 cc. dioxan, and the resulting solution was hydrogenated in the presence of 3 gm. Raney nickel under a pressure of 720 mm. Hg and at a temperature of 17 C. 5410 cc. hydrogen were consumed (calculated quantity: 5480 cc.). The dioxan was then distilled off and the residue was recrystallized from gasoline. The hydrogenation product had the structural formula IYIH:

-o rrronrocm 5 gm. of this 4-amino-phenol ether were boiled for 15 minutes with cc. acetic acid anhydride and the mixture was then stirred into water. The substance precipitated thereby was separated on a vacuum filter and filter cake was recrystallized from a 50% aqueous solution of methanol. The reaction product, having the structural formula CH:-CHr-O CH:

and a melting point of 113 to 114 C., was obtained in the form of long, colorless needles.

EXAMPLE 6 Preparation of 2-butyryl-4-N-methyl-N-acetylaminophenyl-fl-methoxy-ethyl ether by method F 23.7 gm. (0.1 mol) 2-butyryl-4-aminophenyl-fi-methoXy-ethyl ether and 13 gm. potassium carbonate were stirred into 50 cc. dimethylformamide and then 14.0 gm. methyliodide (0.1 mol) were added dropwise to the solution. The reaction proceeded with evolution of heat and formation of carbon dioxide. After all of the methyliodide had been added, the reaction mixture was heated for -1 hour at 60 C., whereupon it was cooled. The raw reaction product was then precipitated by adding water to the reaction mixture. The precipitate was separated on the vacuum filter and the filter cake was subjected to preliminary purification by dissolving it in 2 N hydrochloric acid and reprecipitating it from solution with concentrated ammonia. After again separating the precipitate on a vacuum filter, the filter cake was recrystallized from gasoline, yielding 2-butyryl-4-methy1aminophenylfi-methoxy-ethyl ether, having the structural formula lTHCHa and a melting point of 72 to 74 C.,- in the form of golden yellow, brilliant leaflets.

5.0 gm. of this compound were then boiled with 5 cc. acetic acid anhydride for 10 minutes and the resulting solution was poured into water while it was still hot. The oily substance precipitated thereby soon crystallized throughout and was then recrystallized from aqueous methatiol; The reaction product, having the structural formula 0 ll- C-CHz-CHz-CHa and a melting point of to 96 C., was obtained in the form of brilliant silver leaflets.

EXAMPLE 7 Preparation of 2-acetyl-4-acetaminophenyl-B-acetoxyethyl ether by method G NH-C 0 OH:

ll 0-0 H:

and a nielting point of 136 to 137 C. in the form of white crystals.

EXAMPLE 8 Preparation of 2-acetyI-S-acetaminopheI1yl-fl-mezhoxyethyl ether by method A A mixture of 60 gm. (0.278 mol) of the sodium salt of 2-acetyl-S-acetamino-phenol, 300 cc. 4-butanol and 80 gm. (0.278 mol) p-toluene-sulfonic acid-B-methoxyethyl ester was boiled for 3 hours, accompanied by stirring. The reaction mixture was allowed to cool to room temperature and was then admixed with water and shaken. 'Ihe butanol layer was separated and dried with potassium carbonate. The butanol was distilled ofi and the residue was recrystallized from xylene. The purified reaction product, having the structural formula ll. C-CH:

o-oHT-om-o on,

and a melting point of 128 to 130 C., was obtained in the form of white crystals.

The following table lists additional compounds of the Formula I above which were prepared. In each case the table defines the substituent radicals X, R through R and the integer n, and gives the reactants used, the melting point of the reaction product and the procedure used in, preparing; the particular compound.

Ex. I

Reaetants Prepared process analogous to Ex. N o.-

2-butyryl-4-amino-phenyl-5; methoxyethyl 'ether and ethyleneoxide. 2-butyryl-4-amino-phenyl-5r methoxyethyl ether and propylene oxide.

2-butyryl-4-amlno-phenyl-B- methoxy-et-hyl ether and benzene-sulfonic' acid-fimethoxy-ethylester.

2-butyryl-4-amino-phenyl-B: methoxy-ethyl ether and allyl chloride.

2-pelargonyl-4-acetamino-phe- 1101 and benzene sulfonic acid- B-methoxy-ethylester.

2-acetyl--acetamino ii-bromophenol and p-toluene-sulionic acid-B-methoxy-ethylester.

2-propiony1-4-acetamino-phenot and p-toluene-sulfonie acid-fl- [B'- (fl-n-butoxy) ethoxy]-ethoxy-ethylester.

2 acetyl 4 -nitro 5 methoxy phenol and hydrogen.

2-acetyl-4-amino-5-methoxyphenyl-fi-methoxy-ethyl ether and acetic acid anhydride.

2 acetyl 5 acetamino sodium phenolate and p-toluene-sulionic acid-B-ethoxy-ethyl ester.

2 -aeetyl- 5 -acetamino -sodium phenolate and p-toluene-sul-. ionic aeid-B-chloro-ethyl ester.

2 acetyl- 5 -aeetamino -sodium phenolate and p'toluene-sultonic aeid-y-chloro-propyl ester.

2 propionyl- 5- propionamino sodium phenolate and ptoluene-sulfonic aeid-fl-methoxyethyl ester.

2-propionyl-5-propion -aminosodium phenolate and p: toluene-sulfonic acid-B- ethoxy-ethyl ester.

2-propiony1-5-acetamino-sodium phenolate and p-toluenesulfonic acid-B-chloroethyl ester.

Z-propionyl-5-acetamino-sodium phenolate and p-toluenesulionie acid-y-chloropropyl ester.

2-butyryl-5-acetamino-sodium phenolate and p-toluene-sul: ionic acid-fi-methoxy ethyl ester.

2 acetyl 5 acetamino phenol and ethylene-oxide.

2 acetyl 5 acetamino phenol and p-toluene-sulfonic acidfi-methoxy-ethyl ester.

emonrcniomznn 4-NHCOCH3 4-NHCOCIEI3- 4-NHC OGHa 4-NHz 4-NHOOCH3 s-nnooonz E-NHCOOHz.

S-NHOOOH:

5-NHO 001120133"--.

S-NHCOCHzCHs 5-NHC 0 CH3 5-NHOOCHa fi-NHCOCHa .l

5-NHCOOH3- 5-Nnoocn3 CHr-CH5.----

CHa

OCH3

O CH;

-OCHi O CH:

1 B. at 0.5 mm'. Hg: 212 0.

While 1 have illustrated the present invention with the aid of certain specific embodiments thereof, it willbe readily apparent to those skilled in the art that the 60 invention is not limited to these embodiments and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

I claim: 7 V 1. Compounds having the structural formula wherein X is selected from the group consisting of 4- amino and S-amino radicals of the formula hydroxy-substituted lower alkanoyl,

R is selected from the group consisting of alkyl with 1 to 11 carbon atoms and phenyl, R is selected from the group consisting of hydrogen,

halogen and lower alkoxy,

R is hydrogen,

R is selected from the group consisting of hydrogen,

halogen and lower alkyl,

R, is selected from the group consisting of halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, and halogensubstituted methyl, and

n is a whole number from O to 2, inclusive.

2. 2-propiony1-4-acetylaminophenyl-p-methoxy ethyl ether.

3. 2-propionyl-4-acetylaminophenyl B chloro ethyl ether.

4. 2-propionyl-4-acetylaminophenyl B (13' ethoxy)- ethoxy-ethyl ether.

5. 2-butyryl-4-acetylaminophenyl p methoxy ethyl ether.

8. 2-propionyl-5-acetylaminophenyl 7 chloro-propyl 2 ether.

14 9. 2-butyry1-4-(B-hydroxy-propyl) aminophenyl pmethoxy-ethyl ether.

References Cited in the file of this patent UNITED STATES PATENTS 2,921,961 Mueller et al. Jan. 19, 1960 FOREIGN PATENTS 670,584 Germany Ian. 20, 1939 OTHER REFERENCES Kunckell: Chemische Berichte," vol. 34, pages 124- 6. 2-butyryl-4-dimethylaminophenyl-fi-methoxy ethyl 15 128 (1901)- Mathieson et al.: Journal of the Chemical Society, part II, pages 1133-1137 (1949).

Julia: Societe Chemique de France, Bulletin T. 19,

0 pages 639-642 (1952). 

1. COMPOUNDS HAVING THE STRUCTURAL FORMULA 